The proportion of the total US population over age 80 is rising exponentially, thus increasing the frequency of those who are at highest risk for developing dementias such as Alzheimer's disease. The proposed research addresses this major public health challenge by studying a population of individuals who seem to avoid degenerative disease processes. Our center identified a unique group of SuperAgers, individuals over age 80 who demonstrate superior memory functioning and thrive in daily life. The goal of the SuperAging Study at Northwestern University is to identify the anatomic, histopathologic, neuropsychological, psychosocial, and genetic factors that explain preserved cognition in these long-lived persons. One possible mechanism may be linked with resistance to pathologic brain changes that occur with normal aging and cognitive decline. Interestingly, at our Center, preliminary analysis of cortical thickness measures from MRI scans of SuperAgers compared to control groups found greater thickness of the anterior cingulate cortex (ACC). Additionally, preliminary post-mortem qualitative examination of SuperAging brains revealed remarkable findings: (1) virtual absence of plaques and tangles-hallmarks of Alzheimer's disease- in the ACC and (2) increased density of von Economo neurons (VENS), a unique feature of the higher primate ACC implicated in complex reasoning and higher-order cognition. The goal of this proposal is to investigate structural and pathologic features of the cingulate cortex in SuperAgers, as this region is shown to mediate executive functions that facilitate memory. Aim 1 will employ a neuroimaging approach to conduct a detailed region-of-interest analysis of the cingulate in large groups of SuperAgers and controls to identify cingulate areas that may represent anatomic substrates unique to SuperAging. Given prior findings, we hypothesize that SuperAgers will have increased thickness in ACC vs. other cingulate regions compared to controls. Aim 2 will employ a histopathologic approach to quantitate features of post-mortem cingulate as they pertain to aging, including markers of plaques and tangles and counts of VENs, in specimens from SuperAgers and controls. Based on preliminary findings, the frequency of pathologic features in the cingulate is expected to be lower in SuperAgers compared to controls~ VEN density, however, is expected to be greatest in SuperAgers. Relationships between anatomic measures in Aim 1 and performance on cognitive tests will be analyzed to identify brain-behavior relationships~ relationships between histopathologic features in Aim 2 and cognitive performance will also be analyzed. Findings from this multidisciplinary study will provide valuable information on neural mechanisms underlying preservation of superior cognitive functioning in old age. The SuperAging Study, of which this project is an integral part, is highly translational as findings will help reveal the neurobiologic constituents f aging that can ultimately guide treatments for dementias. Advanced training in neuroimaging, histopathology, and cognitive assessment are critical for attainment of these goals.